IUPHAR - invited review - Ibogaine - A legacy within the current renaissance of psychedelic therapy.

Ibogaine is a powerful psychoactive substance that not only alters perception, mood and affect, but also stops addictive behaviors. Ibogaine has a very long history of ethnobotanical use in low doses to combat fatigue, hunger and thirst and, in high doses as a sacrament in African ritual contexts. In the 1960's, American and European self-help groups provided public testimonials that a single dose of ibogaine alleviated drug craving, opioid withdrawal symptoms, and prevented relapse for weeks, months and sometimes years. Ibogaine is rapidly demethylated by first-pass metabolism to a long-acting metabolite noribogaine. Ibogaine and its metabolite interact with two or more CNS targets simultaneously and both drugs have demonstrated predictive validity in animal models of addiction. Online forums endorse the benefits of ibogaine as an "addiction interrupter" and present-day estimates suggest that more than ten thousand people have sought treatment in countries where the drug is unregulated. Open label pilot studies of ibogaine-assisted drug detoxification have shown positive benefit in treating addiction. Ibogaine, granted regulatory approval for human testing in a Phase 1/2a clinical trial, joins the current landscape of psychedelic medicines in clinical development.

Potent Anti-amoebic Effects of Ibogaine, Voacangine and the Root Bark Alkaloid Fraction of Tabernaemontana arborea.

Plants of Tabernaemontana species have several pharmacological activities including antimicrobial effects. Amoebiasis continues to be a public health problem, with increasing evidence of resistance to metronidazole. In this study, we assessed the effect of the alkaloid fraction of T. arborea root bark and the alkaloids ibogaine and voacangine on the viability and infectivity of Entamoeba histolytica trophozoites. Cultures were exposed to 0.1 - 10 µg/mL for 24, 48 and 72 h, and viability was then determined using a tetrazolium dye reduction assay and type of cellular death analyzed by flow cytometry. Results showed that the alkaloid fraction, but mainly ibogaine and voacangine alkaloids, exhibited potent dose-dependent anti-amoebic activity at 24 h post-exposure (IC50 4.5 and 8.1 µM, respectively), comparable to metronidazole (IC50 6.8 µM). However, the effect decreased after 48 and 72 h of exposure to concentrations below 10 µg/mL, suggesting that the alkaloids probably were catabolized to less active derivatives by the trophozoites. The treatment of trophozoites with the IC50 s for 24 h induced significant morphological changes in the trophozoites, slight increase in granularity, and death by apoptonecrosis. The capacity of T. arborea alkaloids to inhibit the development of amoebic liver abscesses in hamsters was evaluated. Results showed that even when the treatments reduced the number of amoebic trophozoites in tissue sections of livers, they were unable to limit the formation of abscesses, suggesting their rapid processing to inactive metabolites. This work leaves open the possibility of using Tabernaemontana alkaloids as a new alternative for amoebiasis control.

Antiproliferative and Microtubule-stabilizing Activities of Two Iboga-vobasine Bisindoles Alkaloids from Tabernaemontana corymbosa in Colorectal Adenocarcinoma HT-29 Cells.

Two iboga-vobasine bisindoles, 16'-decarbomethoxyvoacamine (1: ) and its 19,20-dihydro derivative, 16'-decarbomethoxydihydrovoacamine (2: ) from Tabernaemontana corymbosa exhibited potent cytotoxicity against the human colorectal adenocarcinoma HT-29 cells in our previous studies. Bisindoles 1: and 2: selectively inhibited the growth of HT-29 cells without significant cytotoxicity to normal human colon fibroblasts CCD-18Co. Treatment with bisindoles 1: and 2: suppressed the formation of HT-29 colonies via G0/G1 cell cycle arrest and induction of mitochondrial apoptosis. Owing to its higher antiproliferative activity, bisindole 2: was chosen for the subsequent studies. Bisindole 2: inhibited the formation of HT-29 spheroids (tumor-like cell aggregates) in 3D experiments in a dose-dependent manner, while an in vitro tubulin polymerization assay and molecular docking analysis showed that bisindole 2: is a microtubule-stabilizing agent which is predicted to bind at the ß-tubulin subunit at the taxol-binding site. The binding resulted in the generation of ROS, which consequently activated the oxidative stress-related cell cycle arrest and apoptotic pathways, viz., JNK/p38, p21Cip1/Chk1, and p21Cip1/Rb/E2F, as shown by microarray profiling.

Identification and Validation of VEGFR2 Kinase as a Target of Voacangine by a Systematic Combination of DARTS and MSI.

Although natural products are an important source of drugs and drug leads, identification and validation of their target proteins have proven difficult. Here, we report the development of a systematic strategy for target identification and validation employing drug affinity responsive target stability (DARTS) and mass spectrometry imaging (MSI) without modifying or labeling natural compounds. Through a validation step using curcumin, which targets aminopeptidase N (APN), we successfully standardized the systematic strategy. Using label-free voacangine, an antiangiogenic alkaloid molecule as the model natural compound, DARTS analysis revealed vascular endothelial growth factor receptor 2 (VEGFR2) as a target protein. Voacangine inhibits VEGFR2 kinase activity and its downstream signaling by binding to the kinase domain of VEGFR2, as was revealed by docking simulation. Through cell culture assays, voacangine was found to inhibit the growth of glioblastoma cells expressing high levels of VEGFR2. Specific localization of voacangine to tumor compartments in a glioblastoma xenograft mouse was revealed by MSI analysis. The overlap of histological images with the MSI signals for voacangine was intense in the tumor regions and showed colocalization of voacangine and VEGFR2 in the tumor tissues by immunofluorescence analysis of VEGFR2. The strategy employing DARTS and MSI to identify and validate the targets of a natural compound as demonstrated for voacangine in this study is expected to streamline the general approach of drug discovery and validation using other biomolecules including natural products.

Ibogaine and Subjective Experience: Transformative States and Psychopharmacotherapy in the Treatment of Opioid Use Disorder.

This article examines the therapeutic potential of ibogaine, a powerful oneiric alkaloid derived from Tabernanthe iboga, through exploring the subjective experiences of 44 participants from two observational treatment studies for opioid use disorder. Following treatment with ibogaine HCl, the participants (Mexico, n = 30; New Zealand, n = 14) completed the States of Consciousness Questionnaire (SCQ) to quantify the magnitude of their psychotropic experience. Participants were asked to provide written transcripts of their experiences, with those supplied being analyzed thematically through an iterative process, to produce a set of coded themes. Mean SCQ scores in many domains exceeded 0.6, the cutoff score for a "complete mystical experience," with 43% of participants achieving this in more than five of seven domains. Qualitative data described multiple phenomenological themes, including auditory and visual phenomena. Ibogaine's strong oneiric action promoted cyclic visions leading to confronting realizations involving remorse and regret for participants' actions towards others, but also release from feelings of guilt and worthlessness. Many participants reported feeling a sense of spiritual transformation. We propose that the reported experiences support the meaningfulness of ibogaine's oneiric effects as a discrete element in its capacity for healing, which is distinct from pharmacological actions associated with reduced withdrawal and craving.

Vobasinyl-Iboga Alkaloids from Tabernaemontana elegans: Cell Cycle Arrest and Apoptosis-Inducing Activity in HCT116 Colon Cancer Cells.

Phytochemical investigation of the roots of the African medicinal plant Tabernaemontana elegans led to the isolation of three new (1-3) and two known (4 and 5) bisindole alkaloids of the vobasinyl-iboga type. The structures of 1-3 were assigned by spectroscopic methods, mainly using 1D and 2D NMR experiments. All of the isolated compounds were evaluated for their cytotoxicity against HCT116 colon and HepG2 liver carcinoma cells by the MTS metabolism assay. Compounds 1-3 and 5 were found to be cytotoxic to HCT116 colon cancer cells, displaying IC50 values in the range 8.4 to >10 µM. However, the compounds did not display significant cytotoxicity against HepG2 cancer cells. The cytotoxicity of compounds 1-3 and 5 was corroborated using a lactate dehydrogenase assay. Hoechst staining and nuclear morphology assessment and caspase-3/7 activity assays were also performed for investigating the activity of compounds 1-3 and 5 as apoptosis inducers. The induced inhibition of proliferation of HCT116 cells by compounds 1 and 2 was associated with G1 phase arrest, while compounds 3 and 5 induced G2/M cell cycle arrest. These results showed that the new vobasinyl-iboga alkaloids 1-3 and compound 5 are strong inducers of apoptosis and cell cycle arrest in HCT116 colon cancer cells.

Pharmacokinetics of hERG Channel Blocking Voacangine in Wistar Rats Applying a Validated LC-ESI-MS/MS Method.

Herbal preparations from Voacanga africana are used in West and Central African folk medicine and are also becoming increasingly popular as a legal high in Europe. Recently, the main alkaloid voacangine was found to be a potent human ether-à-go-go-related gene channel blocker in vitro. Blockage of this channel might imply possible cardiotoxicity. Therefore, the aim of this study was to characterise voacangine in vivo to assess its pharmacokinetics and to estimate if further studies to investigate its cardiotoxic risk are required. Male Wistar rats received different doses of voacangine as a pure compound and as a hydro-ethanolic extract of V. africana root bark with a quantified amount of 9.71 % voacangine. For the obtained data, a simultaneous population pharmacokinetics model was successfully developed, comprising a two-compartment model for i. v. dosing and a one-compartmental model with two first-order absorption rates for oral dosing. The absolute bioavailability of voacangine was determined to be 11-13 %. Model analysis showed significant differences in the first absorption rate constant for voacangine administered as a pure compound and voacangine from the extract of V. africana. Taking into account the obtained low bioavailability of voacangine, its cardiotoxic risk might be neglectable in healthy consumers, but may have a serious impact in light of drug/drug interactions and impaired health conditions.

hERG Blockade by Iboga Alkaloids.

The iboga alkaloids are a class of naturally occurring and synthetic compounds, some of which modify drug self-administration and withdrawal in humans and preclinical models. Ibogaine, the prototypic iboga alkaloid that is utilized clinically to treat addictions, has been associated with QT prolongation, torsades de pointes and fatalities. hERG blockade as IKr was measured using the whole-cell patch clamp technique in HEK 293 cells. This yielded the following IC50 values: ibogaine manufactured by semisynthesis via voacangine (4.09 ± 0.69 µM) or by extraction from T. iboga (3.53 ± 0.16 µM); ibogaine's principal metabolite noribogaine (2.86 ± 0.68 µM); and voacangine (2.25 ± 0.34 µM). In contrast, the IC50 of 18-methoxycoronaridine, a product of rational synthesis and current focus of drug development was >50 µM. hERG blockade was voltage dependent for all of the compounds, consistent with low-affinity blockade. hERG channel binding affinities (K i) for the entire set of compounds, including 18-MC, ranged from 0.71 to 3.89 µM, suggesting that 18-MC binds to the hERG channel with affinity similar to the other compounds, but the interaction produces substantially less hERG blockade. In view of the extended half-life of noribogaine, these results may relate to observations of persistent QT prolongation and cardiac arrhythmia at delayed intervals of days following ibogaine ingestion. The apparent structure-activity relationships regarding positions of substitutions on the ibogamine skeleton suggest that the iboga alkaloids might provide an informative paradigm for investigation of the structural biology of the hERG channel.

[Psychedelics and quasi-psychedelics in the light of contemporary research: medical cannabis, MDMA, salvinorin A, ibogaine and ayahuasca]. / Pszichedelikumok és kvázi-pszichedelikumok a modern kutatások tükrében: orvosi kannabisz, MDMA, szalvinorin A, ibogain és ayahuasca.

In lack of professional research and appropriate concepts our scientific knowledge of psychedelic agents is limited. According to the long-held official view these drugs are entirely harmful and have no medical use. However, a recent surge of clinical and pharmacological studies in the field indicates that many psychedelic-like agents have therapeutic potentials under proper circumstances. In this paper, from a biomedical and psychological perspective, we provide a brief review of the general effects and promising treatment uses of medical cannabis, 3,4-methylenedioxy-methamphetamine (MDMA), salvinorin A, ibogaine and the dimethyltryptamine-(DMT)-containing ayahuasca. In Hungary - similarly to many other countries - these compounds are classified as "narcotic drugs" and their research is difficult due to strict regulations.

Noribogaine is a G-protein biased κ-opioid receptor agonist.

Noribogaine is the long-lived human metabolite of the anti-addictive substance ibogaine. Noribogaine efficaciously reaches the brain with concentrations up to 20 µM after acute therapeutic dose of 40 mg/kg ibogaine in animals. Noribogaine displays atypical opioid-like components in vivo, anti-addictive effects and potent modulatory properties of the tolerance to opiates for which the mode of action remained uncharacterized thus far. Our binding experiments and computational simulations indicate that noribogaine may bind to the orthosteric morphinan binding site of the opioid receptors. Functional activities of noribogaine at G-protein and non G-protein pathways of the mu and kappa opioid receptors were characterized. Noribogaine was a weak mu antagonist with a functional inhibition constants (Ke) of 20 µM at the G-protein and ß-arrestin signaling pathways. Conversely, noribogaine was a G-protein biased kappa agonist 75% as efficacious as dynorphin A at stimulating GDP-GTP exchange (EC50=9 µM) but only 12% as efficacious at recruiting ß-arrestin, which could contribute to the lack of dysphoric effects of noribogaine. In turn, noribogaine functionally inhibited dynorphin-induced kappa ß-arrestin recruitment and was more potent than its G-protein agonistic activity with an IC50 of 1 µM. This biased agonist/antagonist pharmacology is unique to noribogaine in comparison to various other ligands including ibogaine, 18-MC, nalmefene, and 6'-GNTI. We predict noribogaine to promote certain analgesic effects as well as anti-addictive effects at effective concentrations>1 µM in the brain. Because elevated levels of dynorphins are commonly observed and correlated with anxiety, dysphoric effects, and decreased dopaminergic tone, a therapeutically relevant functional inhibition bias to endogenously released dynorphins by noribogaine might be worthy of consideration for treating anxiety and substance related disorders.

Ex vivo effects of ibogaine on the activity of antioxidative enzymes in human erythrocytes.

ETHNOPHARMACOLOGICAL RELEVANCE: Ibogaine is a naturally occurring alkaloid with psychotropic and metabotropic effects, derived from the bark of the root of the West African Tabernanthe iboga plant. The tribes of Kongo basin have been using iboga as a stimulant, for medicinal purposes, and in rite of passage ceremonies, for centuries. Besides, it has been found that this drug has anti-addictive effects. AIM OF THE STUDY: Previous studies have demonstrated that ibogaine changed the quantity of ATP and energy related enzymes as well as the activity of antioxidant enzymes in cells thus altering redox equilibrium in a time manner. In this work, the mechanism of its action was further studied by measuring the effects of ibogaine in human erythrocytes in vitro on ATP liberation, membrane fluidity and antioxidant enzymes activity. MATERIALS AND METHODS: Heparinized human blood samples were incubated with ibogaine (10 and 20 µM) at 37°C for 1h. Blood plasma was separated by centrifugation and the levels of ATP and uric acid were measured 10 min after the addition of ibogaine using standard kits. The activity of copper-zinc superoxide dismutase (SOD1), catalase (CAT), glutathione peroxidase (GSH-Px) and glutathione reductase (GR) were measured in erythrocytes after incubation period. The stability of SOD1 activity was further tested through in vitro incubation with H2O2 and scanning of its electrophoretic profiles. Membrane fluidity was determined using an electron paramagnetic resonance spin-labelling method. RESULTS: Results showed that ibogaine treatment of erythrocytes in vitro increased ATP concentration in the blood plasma without changes in neither erythrocytes membrane fluidity nor uric acid concentration. Ibogaine also increased SOD1 activity in erythrocytes at both doses applied here. Treatment with 20 µM also elevated GR activity after in vitro incubation at 37°C. Electrophoretic profiles revealed that incubation with ibogaine mitigates H2O2 mediated suppression of SOD1 activity. CONCLUSION: Some of the effects of ibogaine seem to be mediated through its influence on energy metabolism, redox active processes and the effects of discrete fluctuations of individual reactive oxygen species on different levels of enzyme activities. Overall, ibogaine acts as a pro-antioxidant by increasing activity of antioxidative enzymes and as an adaptagene in oxidative distress.

Screening and identification of neuroprotective compounds relevant to Alzheimer׳s disease from medicinal plants of S. Tomé e Príncipe.

ETHNOPHARMACOLOGICAL RELEVANCE: Alzheimer׳s disease (AD) neuropathology is strongly associated with the activation of inflammatory pathways, and long-term use of anti-inflammatory drugs reduces the risk of developing the disease. In S. Tomé e Príncipe (STP), several medicinal plants are used both for their positive effects in the nervous system (treatment of mental disorders, analgesics) and their anti-inflammatory properties. The goal of this study was to determine whether a phenotypic, cell-based screening approach can be applied to selected plants from STP (Voacanga africana, Tarenna nitiduloides, Sacosperma paniculatum, Psychotria principensis, Psychotria subobliqua) in order to identify natural compounds with multiple biological activities of interest for AD therapeutics. MATERIALS AND METHODS: Plant hydroethanolic extracts were prepared and tested in a panel of phenotypic screening assays that reflect multiple neurotoxicity pathways relevant to AD-oxytosis in hippocampal nerve cells, in vitro ischemia, intracellular amyloid toxicity, inhibition of microglial inflammation and nerve cell differentiation. HPLC fractions from the extract that performed the best in all of the assays were tested in the oxytosis assay, our primary screen, and the most protective fraction was analyzed by mass spectrometry. The predominant compound was purified, its identity confirmed by ESI mass spectrometry and NMR, and then tested in all of the screening assays to determine its efficacy. RESULTS: An extract from the bark of Voacanga africana was more protective than any other plant extract in all of the assays (EC50s≤2.4 µg/mL). The HPLC fraction from the extract that was most protective against oxytosis contained the alkaloid voacamine (MW=704.90) as the predominant compound. Purified voacamine was very protective at low doses in all of the assays (EC50s≤3.4 µM). CONCLUSION: These findings validate the use of our phenotypic screening, cell-based assays to identify potential compounds to treat AD from plant extracts with ethnopharmacological relevance. Our study identifies the alkaloid voacamine as a major compound in Voacanga africana with potent neuroprotective activities in these assays.

Psychedelics as medicines for substance abuse rehabilitation: evaluating treatments with LSD, Peyote, Ibogaine and Ayahuasca.

Substances known as psychedelics, hallucinogens and entheogens have been employed in ethnomedical traditions for thousands of years, but after promising uses in the 1950's and 1960's they were largely prohibited in medical treatment and human research starting in the 1970's as part of the fallout from the war on drugs. Nonetheless, there are a number of studies which suggest that these substances have potential applications in the treatment of addictions. While these substances are generally classified as Schedule I, alleging no established medical uses and a high drug abuse potential, there is nonetheless evidence indicating they might be safe and effective tools for short term interventions in addictions treatment. Evidence suggests that the psychedelics have a much greater safety profile than the major addictive drugs, having extremely low levels of mortality, and producing little if any physical dependence. This paper reviews studies evaluating the use of LSD, peyote, ibogaine and ayahuasca in the treatment of dependencies and the possible mechanisms underlying the indications of effectiveness. Evidence suggests that these substances help assist recovery from drug dependency through a variety of therapeutic mechanisms, including a notable "after-glow" effect that in part reflects their action on the serotonin neurotransmitter system. Serotonin has been long recognized as central to the psychedelics' well-known phenomenological, physical, emotional and cognitive dynamics. These serotonin-based dynamics are directly relevant to treatment of addiction because of depressed serotonin levels found in addict populations, as well as the role of serotonin as a neuromodulators affecting many other neurotransmitter systems.

Anti-addiction drug ibogaine inhibits hERG channels: a cardiac arrhythmia risk.

Ibogaine, an alkaloid derived from the African shrub Tabernanthe iboga, has shown promising anti-addictive properties in animals. Anecdotal evidence suggests that ibogaine is also anti-addictive in humans. Thus, it alleviates drug craving and impedes relapse of drug use. Although not licensed as therapeutic drug, and despite evidence that ibogaine may disturb the rhythm of the heart, this alkaloid is currently used as an anti-addiction drug in alternative medicine. Here, we report that therapeutic concentrations of ibogaine reduce currents through human ether-a-go-go-related gene potassium channels. Thereby, we provide a mechanism by which ibogaine may generate life-threatening cardiac arrhythmias.

Effect of Iboga alkaloids on µ-opioid receptor-coupled G protein activation.

OBJECTIVE: The iboga alkaloids are a class of small molecules defined structurally on the basis of a common ibogamine skeleton, some of which modify opioid withdrawal and drug self-administration in humans and preclinical models. These compounds may represent an innovative approach to neurobiological investigation and development of addiction pharmacotherapy. In particular, the use of the prototypic iboga alkaloid ibogaine for opioid detoxification in humans raises the question of whether its effect is mediated by an opioid agonist action, or if it represents alternative and possibly novel mechanism of action. The aim of this study was to independently replicate and extend evidence regarding the activation of µ-opioid receptor (MOR)-related G proteins by iboga alkaloids. METHODS: Ibogaine, its major metabolite noribogaine, and 18-methoxycoronaridine (18-MC), a synthetic congener, were evaluated by agonist-stimulated guanosine-5´-O-(γ-thio)-triphosphate ([(35)S]GTPγS) binding in cells overexpressing the recombinant MOR, in rat thalamic membranes, and autoradiography in rat brain slices. RESULTS AND SIGNIFICANCE: In rat thalamic membranes ibogaine, noribogaine and 18-MC were MOR antagonists with functional Ke values ranging from 3 uM (ibogaine) to 13 uM (noribogaine and 18MC). Noribogaine and 18-MC did not stimulate [(35)S]GTPγS binding in Chinese hamster ovary cells expressing human or rat MORs, and had only limited partial agonist effects in human embryonic kidney cells expressing mouse MORs. Ibogaine did not did not stimulate [(35)S]GTPγS binding in any MOR expressing cells. Noribogaine did not stimulate [(35)S]GTPγS binding in brain slices using autoradiography. An MOR agonist action does not appear to account for the effect of these iboga alkaloids on opioid withdrawal. Taken together with existing evidence that their mechanism of action also differs from that of other non-opioids with clinical effects on opioid tolerance and withdrawal, these findings suggest a novel mechanism of action, and further justify the search for alternative targets of iboga alkaloids.

Determination of antiplasmodial activity and binding affinity of selected natural products towards PfTrxR and PfGR.

In our study, the binding affinities of selected natural products towards PfTrxR, PfGR, human TrxR and human GR were determined using a mass spectrometry based ligand binding assay. The in vitro antimalarial activity and cytotoxicity of these ligands were also determined. Catharanthine, 11-(OH)-coronaridine, hernagine, vobasine and hispolone displayed antiplasmodial activity against PfK1 (IC50 = 0.996-3.63 microg/mL).

3'-R/S-hydroxyvoacamine, a potent acetylcholinesterase inhibitor from Tabernaemontana divaricata.

Guided by the acetylcholinesterase inhibiting activity, the bisindole alkaloid 3'-R/S-hydroxyvoacamine was isolated from a stem extract of Tabernaemontana divaricata, a plant used in Thailand in traditional rejuvenation remedies for improving the memory. The structure of the alkaloid was elucidated by extensive use of NMR spectroscopy and the complete assignment of the (1)H and (13)C NMR spectra is reported. The alkaloid acted as a non-competitive inhibitor against AChE with an IC50 value of 7.00±1.99 µM. An HPLC method was developed for the quantitative analysis of the AChE inhibitor. It suggested that there was 12.4% (w/w) of 3'-R/S-hydroxyvoacamine in the alkaloid enriched fraction of T. divaricata stem.

Metabolic plasticity and the energy economizing effect of ibogaine, the principal alkaloid of Tabernanthe iboga.

ETHNOPHARMACOLOGICAL RELEVANCE: The root bark of iboga plant-Tabernanthe iboga has been used traditionally in Central Africa as a psychoactive substance in religious rituals, while in smaller doses it is appreciated due to its stimulant properties. The iboga root bark, iboga extract or pure ibogaine are being recognized in the West as an anti-addiction remedy and their use is increasing. AIM OF THE STUDY: Our previous studies have demonstrated a transient ATP pool reduction under ibogaine accompanied by the induction of energy metabolism related enzymes. The present study aimed to find the cause of this energy deprivation and to foresee its immediate and long-term impact on metabolism. The overall project is designed to disclose the common mechanism of action at these seemingly diverse indications for iboga use, to predict eventual adverse effects and to build the grounds for its safe and beneficial utilization. MATERIALS AND METHODS: The rate of carbon dioxide (CO(2)) as a marker of energy metabolism in stationary yeast model under aerobic conditions in the presence of ibogaine at concentration of 1, 4 and 20mg/l was measured for 5h by gas chromatography. The overall oxidative load was determined fluorimetrically by 2',7'-dichlorofluorescein diacetate (H(2)DCFDA) and in vitro antioxidant properties of ibogaine were defined by 1,1-diphenyl-2-picrylhydrazyl (DPPH) test. RESULTS: The CO(2) production under ibogaine was temporarily increased in a dose dependent manner. The increased energy consumption as an early effect of ibogaine was proven by the fact that in spite of energy mobilization, the ATP pool has been simultaneously decreased. Although increased cellular respiration co-produces reactive oxygen species (ROS), the overall oxidative load was significantly lowered by ibogaine. Since ibogaine does not show any significant in vitro antioxidant properties, the results indicate its stimulating influence on physiological oxidative stress defence system. CONCLUSION: Ibogaine triggers remodeling of the housekeeping metabolism. Under the initial energy cost it results in increased efficacy of physiological antioxidative systems, which reduce oxidative damage and lowers basal metabolic needs. Together with induced catabolic enzymes they set a new metabolic equilibrium that saves energy and makes it easily available in case of extra needs. While healthy organism profits from improved fitness and mental performance and can withstand higher stress without risking a disease, due to the same principle ibogaine provides beneficial support at the recovery after diseases including addiction syndrome.

Serotonergic hallucinogens and emerging targets for addiction pharmacotherapies.

Only time will tell if serotonergic hallucinogen-assisted psychotherapy treatment paradigms for SUDs will prove to be safe and effective in double-blind, placebo-controlled clinical trials. If they are, they would truly constitute a novel psychopharmacologic-psychosocial treatment paradigm to treat addictive disorders, although the risk of adverse psychological events would have to be controlled through a careful screening process and the risk of misuse of the substances or developing use syndromes would have to be considered, although the overall risk would be low because, as mentioned, SHs are unlike all other drugs of abuse in that they do not appear to produce dependence syndromes. There effects on the NA and DA range from inhibition to slight activation, all this without producing addiction. The ability of these medicinal tools to treat a range of addictive, psychiatric, and existential disorders is remarkable in scope and possibility. They truly represent a potential paradigmatic shift within the field of psychiatry, too interesting to not explore further.